The invention relates to methods of using pharmaceutically-active fused heterobicyclic compounds to treat or prevent disorders and conditions mediated by the histamine H3 receptor.
The histamine H3 receptor is located as a presynaptic autoreceptor in the central nervous system and as a presynaptic heteroreceptor on serotonergic, noradrenergic, dopaminergic, and cholinergic neurons. The histamine H3 receptor is also located peripherally in tissues such as vascular smooth muscle cells.
Proposed uses of histamine H3 antagonists include the treatment or prevention of dementia, Alzheimer""s disease (Panula et al. Abstr. Society Neuroscience, 1995, 21:1977), epilepsy (Yokoyama et al. Eur. J. Pharmacol., 1993, 234:129), sleep/wake disorders (Lin et al., Br. Res., 1990, 523, 325; Monti et al., Eur. J. Pharmacol., 1991,205, 283) including narcolepsy, insomnia, and jet lag, eating disorders (Machidori et al. Brain Research, 1992, 590:180), motion sickness, vertigo, attention deficit hyperactivity disorder, learning and memory disorders (Barnes et al. Abstr. Society Neuroscience, 1993,19:1813), schizophrenia (Schlickeret et al. Naunyn Schmiedeberg""s Arch. Pharmacol., 1996, 353:325), and sequelae associated with post-ischemic reperfusion and hypertension (Imamura et al., J. Pharmacol Expt. Ther., 1994, 271,1259). H3 antagonists are also useful to treat or prevent neurogenic inflammation such as migraine (McLeod et al., Abstr. Society Neuroscience, 1996, 22, 2010), asthma (lchinose et al., Eur. J. Pharmacol., 989,174, 49), obesity, allergic rhinitis, substance abuse, bipolar disorders, manic disorders, and depression. Histamine H3 antagonists alone or in combination with a histamine H1 antagonist are believed to be useful in the treatment of upper airway allergic response or allergic rhinitis (see, e.g., U.S. Pat. Nos. 5,217,986, 5,352,707, and 5,869,479).
As noted, the prior art related to histamine H3 ligands was comprehensively reviewed recently (xe2x80x9cThe Histamine H3 Receptor-A Target for New Drugsxe2x80x9d, Leurs, R., and Timmerman, H., (Editors), Elsevier, 1998). Within this reference the medicinal chemistry of histamine H3 agonists and antagonists was reviewed (see Krause et al. and Phillips et al., respectively). Thus the importance of an imidazole moiety containing only a single substitution in the 4 position was noted together with the deleterious effects of additional substitution on activity. Particularly methylation of the imidazole ring at any of the remaining unsubstituted positions was reported to strongly decrease activity.
More recently several publications have described histamine H3 ligands that do not contain an imidazole moiety. Examples include Ganellin et al Arch. Pharm. (Weinheim,Ger.) 1998, 331, 395; Walczynski et al Arch. Pharm. (Weinheim,Ger.) 1999, 332, 389; Walczynski et al Farmaco 1999, 684; Linney et al J. Med. Chem. 2000, 2362; U.S. Pat. No. 5,352,707; PCT Application WO99/42458, published Aug. 26,1999; and European Patent Application 0978512, published on Feb. 9, 2000.
The invention features the use of the compounds of formula (I) for the treatment and/or prevention of diseases and conditions mediated by the histamine 3 (H3) receptor. 
R is O or S;
R1 is H, C1-4 alkyl, C1-4 alkoxy, Br, Cl, or l;
R2 and R3 are H or xe2x80x94Oxe2x80x94(CH2)mxe2x80x94NR4R5, wherein one of R2 and R3 is H and the other is xe2x80x94Oxe2x80x94(CH2)mxe2x80x94NR4R5, when R3 is xe2x80x94Oxe2x80x94(CH2)mxe2x80x94NR4R5, R2 is independently H, halogen, C1-4 alkyl, or C1-4 alkoxy;
R4 and R5 are the same or different, and are C1-5 alkyl, C cycloalkyl, benzyl, benzyl substituted by C1-4 alkyl, C1-4 alkoxy, Br, Cl, l, or R4 and R5 together with N are piperidyl, pyrrolidyl, imidazolyl, or N-substituted piperazyl, wherein the substituent is C1-4 alkyl, phenyl, or phenyl substituted with C1-3 alkoxy; n is 0 or 1; m is 2-6; with the provisos that when at least one of R and R1 is Ar; and both of R and R1 are not Ar;
or a pharmaceutically acceptable salt, ester, or amide thereof.
Many of the compounds are disclosed generically in U.S. Pat. No. 4,861,897. These compounds were first identified as having antisecretory properties. Additional features of the invention are disclosed in the following description and examples, and in the appended claims.
The invention features pharmaceutically active phenyl-substituted imidazopyridines and methods of making and using them. The description is organized as follows:
A. Terms
B. Compounds
C. Synthetic Methods
D. Uses
E. Synthetic Chemical Examples
F. Biological Examples
G. Other Embodiments
H. claims
A. Terms
The following terms are defined below and by their usage throughout this disclosure.
xe2x80x9cAlkylxe2x80x9d includes straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on.
xe2x80x9cAlkoxyxe2x80x9d includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on.
xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro.
xe2x80x9cpatientxe2x80x9d or xe2x80x9csubjectxe2x80x9d includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient is a human.
xe2x80x9ccompositionxe2x80x9d includes a product comprising the specified ingredients in the specified amounts as well as any product which results directly or indirectly from combinations of the specified ingredients in the specified amounts.
Concerning the various radicals in this disclosure and in the claims, two general remarks are made. The first remark concerns valency. As with all hydrocarbon radicals, whether saturated, unsaturated or aromatic, and whether or not cyclic, straight chain, or branched, and also similarly with all heterocyclic radicals, each radical includes substituted radicals of that type and monovalent, bivalent, and multivalent radicals as indicated by the context of the claims. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent).
Second, radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments. Using xe2x80x9calkylxe2x80x9d as an example, xe2x80x9calkylxe2x80x9d should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, and 3-iodocyclopentyl), hydroxyalkyl, aminoalkyl, nitroalkyl, alkylalkyl, and so on.
B. Compounds
One aspect of the invention features compounds of formula (I) as described in the Summary section above.
Preferred compounds of formula (I) include those compounds wherein: (a) R2 is H; (b) R3 is H; (c) R is O; (d) R1 is H; (e) R is S; (f) n is 1; (g) n is 0; (h) NR4R5 is a cyclic radical; (i) (h) wherein said cyclic radical is piperidyl or pyrrolinyl; (j) each of R4 and R5 is independently selected from ethyl, propyl, isopropyl, and butyl, including n-butyl, sec-butyl, tert-butyl, and isobutyl; (k) m is 2, 3, or 4, and more preferably wherein m is 3 or 4; (l) m is 3; (m) R1 is H, methyl, methoxy, Br, Cl, or l; (n) R2 is H, halogen, methyl, or methoxy, and preferably methyl; (o) or combinations thereof.
Additional preferred compounds include those wherein: R1 is H, methyl, methoxy, Br, Cl, or l; each of R4 and R5 is independently selected from ethyl, propyl, isopropyl, and butyl, or together with N are piperidyl or pyrrolinyl; m is 3 or 4; and each R2 is H, halogen, methyl, or methoxy.
Preferred compounds include: (E)-2-[2-(3-dibutylaminopropoxyphenyl)-ethenyl]benzoxazole; (E)-2-[2-[3-[3-(4-methylpiperazino)propoxy]-phenyl]ethenyl]benzoxazole; (E)-2-[2-(3-dipropylaminopropoxyphenyl)ethenyl]-benzoxazole; (E)-2-[2-(3-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]-benzoxazole; (E)-2-[2-(3-dipropylaminobutoxyphenyl)ethenyl]benzoxazole; (E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; and (E)-2-[2-(3-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]-6-methoxybenzoxazole; and acid addition salts thereof.
Preferred compounds also include: (E)-2-[2-(4-dibutylaminopropoxy-phenyl)ethenyl]benzoxazole; (E)-2-[2-(4-dipropylaminopropoxyphenyl)ethenyl]-benzoxazole; (E)-2-[2-(4-(1H-imidazol-1-yl)propoxyphenyl)ethenyl]-benzoxazole; (E)-2-[2-(4-diethylaminopropoxyphenyl)ethenyl]benzoxazole; (E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]ethenyl]benzoxazole; (E)-2-[2-[4-(3-methylbenzylaminopropoxy)phenyl]ethenyl]benzoxazole; (E)-2-[2-[4-(2-methoxyphenyl)piperazinopropoxyphenyl]ethenyl]benzoxazole; (E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-5-methylbenzoxazole; (E)-2-[2-(4-dibutylaminopropoxyphenyl)ethenyl]-6-methoxybenzoxazole; (E)-2-[2-(4-dibutylaminoethoxyphenyl)ethenyl]benzoxazole; (E)-2-[2-(4-dibutylamino-butoxyphenyl)ethenyl]benzoxazole; (E)-2-[2-(4-piperidinobutoxyphenyl)-ethenyllbenzoxazole; (E)-2-[2-(4-dipropylaminobutoxyphenyl)ethenyl]-benzoxazole; (E)-2-[2-(4-(1H-imidazol-1-yl)butoxyphenyl)ethenyl]benzoxazole; (E)-2-[2-(4-diethylaminobutoxyphenyl)ethenyl]benzoxazole; (E)-2-[2-(4-pyrrolidinobutoxyphenyl)ethenyl]benzoxazole; and (E)-2-[2-(4-(1H-imidazol-1-yl)pentoxyphenyl)ethenyl]benzoxazole; and acid addition salts thereof.
Additional preferred compounds include: (E)-2-[2-(3-chloro-4-dipropylaminobutoxyphenyl)ethenyl]benzoxazole, (E)-2-[2-(3,5-dimethoxy-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole and (E)-2-[2-(3,5-dimethyl-4-dipropylaminopropoxyphenyl)ethenyl]benzoxazole; and acid addition salts thereof.
More preferred compounds include: (E)-2-[2-(4-Piperidinopropoxy-phenyl)ethenyl]benzothiazole; (E)-2-[2-[4-(3-Piperidinopropoxy)phenyl]-ethenyl]benzoxazole; (E)-2-[2-(4-Piperidinobutoxyphenyl)ethenyl]benzoxazole; (E)-2-[2-(4-Diethylaminobutoxyphenyl)ethenyl]benzoxazole; (E)-2-[2-(4-Diethylaminopropoxyphenyl)ethenyl]benzoxazole; (E)-2-[2-(4-Pyrrolinobutoxy-phenyl)ethenyl]benzoxazole; E)-2-[2-(4-Dibutylaminobutoxyphenyl)-ethenyl]benzoxazole; and 2-(4-Dipropylaminopropoxyphenyl)benzothiazole and pharmaceutically acceptable salts thereof.
Other examples of compounds, and methods of making them, are provided in the examples below.
C. Synthetic Methods
The invention provides methods of making the disclosed compounds according to traditional organic synthetic methods as well as matrix or combinatorial synthetic methods. Traditional organic synthetic methods are described in U.S. Pat. No. 4,861,897, which is incorporated by reference in its entirety. Further guidance is found in Chemical Examples 1-8 below.
C. Uses
According to the invention, the disclosed compounds and compositions are useful for the amelioration of symptoms associated with, the treatment of, and/or the prevention of, the following conditions and diseases, or symptoms associated with them: dementia, Alzheimer""s disease, narcolepsy, eating disorders, motion sickness, vertigo, attention deficit hyperactivity disorder, learning and memory disorders, schizophrenia, mild cognitive impairment, upper airway allergic response (allergic rhinitis), insomnia, jet lag, obesity, asthma, neurogenic inflammation, substance abuse, bipolar disorders, manic disorders, and depression. The invention also features pharmaceutical compositions, which include, without limitation, one or more of the disclosed compounds, and a pharmaceutically acceptable carrier or excipient.
1. Dosages
Those skilled in the art will be able to determine, according to known methods, the appropriate dosage for a patient, taking into account factors such as age, weight, general health, the type of symptoms requiring treatment, and the use of other medications. An effective amount means that amount of pharmaceutical reagent (such as a prodrug, metabolic precursor, or active compound) that elicits the biological or medical response desired. In general, a therapeutically effective amount will be between 0.01 and 1000 mg/kg per day, preferably between 0.01 and 250 mg/kg body weight, and daily dosages will be between 0.50 and 5000 mg for an adult subject of normal weight. Capsules, tablets or other formulations (such as liquids and film-coated tablets) may be of between 0.20 and 100 mg, such as 0.20, 0.50, 1, 2, 3, and 10 mg can be administered according to the disclosed methods.
2. Formulations
Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses. Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels or cream), and by inhalation (a buccal or nasal spray) as appropriate depending on the overall health and condition of the patient as determined by a physician or veterinary doctor.
Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption accelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants.
Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
3. Combination Therapy
The present invention also provides compositions and methods useful for the treatment of disorders or conditions modulated, preferably antagonized, by the histamine H3 receptor in combination with compounds that modulate other receptors including, but not limited to, histamine H1 and histamine H2 receptors. The present invention includes compounds and compositions useful in methods of combination therapy for the treatment of diseases or conditions modulated by the histamine H3 receptor in combination with compounds that are selective serotonin re-uptake inhibitors (SSRIs), such as PROZACTM, or are selective norepinephrine uptake inhibitors. Such combination methods include (a) administering the two or more pharmaceutical agents separately formulated and at separate times, and (b) administering the two or more agents simultaneously in a single formulation or in separate formulations administered more or less at the same time. For example, one aspect is a method of treatment comprising administering at least one histamine H3 receptor modulating compound disclosed herein and administering at least one compound selected from a histamine H1 receptor modulating compound, a histamine H2 receptor modulating compound, a selective serotonin reuptake inhibitor (such as PROZAC(trademark)), or a selective norepinephrine uptake inhibiting compound.
4. Related Compounds
The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, acids, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms.
Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C1-8, alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic) amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977, 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C1-6 alkyl amines and secondary di (C1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C1-3alkyl primary amines, and di (C1-2 alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C1-7alkyl, C5-7 cycloalkyl, phenyl, and phenyl(C1-6)alkyl esters. Preferred esters include methyl esters.
The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. See, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., (1999) John Wiley and Sons, NY. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
Hydroxyl Protecting Groups
Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers.
Substituted Methyl Ethers
Examples of substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyidimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
Substituted Ethyl Ethers
Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers
Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, pxe2x80x2-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, xcex1-naphthyidiphenylmethyl, p-methoxyphenyidiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4xe2x80x2-bromophenacyloxy)phenyldiphenylmethyl, 4,4xe2x80x2,4xe2x80x3-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4xe2x80x2,4xe2x80x3-tris(levulinoyloxyphenyl)methyl, 4,4xe2x80x2,4xe2x80x3-tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4 xe2x80x2,4xe2x80x3-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1xe2x80x2-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers
Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyidimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.
Esters
In addition to ethers, a hydroxyl group may be protected as an ester. Examples of esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate(mesitoate)
Carbonates Examples of carbonate protecting groups include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage
Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.
Miscellaneous Esters
Examples of miscellaneous esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate), o-(methoxycarbonyl)benzoate, p-P-benzoate, xcex1-naphthoate, nitrate, alkyl N,N,Nxe2x80x2,Nxe2x80x2-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate
Sulfonates
Examples of sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
Protection for 1,2- and 1,3-Diols
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
Cyclic Ortho Esters
Examples of cyclic ortho esters include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2-dimethoxyethylidene, xcex1-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene derivative, xcex1-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.
Silyl Derivatives
Examples of silyl derivatives include di-t-butylsilylene group, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.
Amino Protecting Groups
Protection for the amino group includes carbamates, amides, and special xe2x80x94NH protective groups.
Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, photolytic cleavage carbamates, urea-type derivatives, and miscellaneous carbamates.
Carbamates
Examples of methyl and ethyl carbamates include methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, and 4-methoxyphenacyl.
Substituted Ethyl
Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2- dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2xe2x80x2- and 4xe2x80x2-pyridyl) ethyl, 2-(N,N-dicycl ohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.
Assisted Cleavage
Examples of assisted cleavage include 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2-(trifluoromethyl)-6-chromonylmethyl.
Photolytic Cleavage
Examples of photolytic cleavage include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl.
Urea-type Derivatives
Examples of urea-type derivatives include phenothiazinyl-(10)-carbonyl derivative, Nxe2x80x2-p-toluenesulfonylaminocarbonyl, and Nxe2x80x2-phenylaminothiocarbonyl.
Miscellaneous Carbamates
Examples of miscellaneous carbamates include t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl methyl, p-decyloxybenzyl, diisopropyl methyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p-(pxe2x80x2-methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and 2,4,6-trimethylbenzyl.
Examples of amides include:
Amides
N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, N-p-phenylbenzoyl.
Assisted Cleavage
N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (Nxe2x80x2-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.
Cyclic Imide Derivatives
N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
Special-NH Protective Groups
Examples of special NH protective groups include
N-Alkyl and N-Aryl Amines
N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3,-acetoxypropyl, N-(1-isopropyl4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine Nxe2x80x2-oxide.
Imine Derivatives
N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, and N-(Nxe2x80x2,Nxe2x80x2-dimethylaminomethylene).
Protection for the Carbonyl Group
Acyclic Acetals and Ketals
Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include 1,3-dioxanes, 5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane, 5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane, O,Oxe2x80x2-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.
Acyclic Dithio Acetals and Ketals
Examples of acyclic dithio acetals and ketals include S,Sxe2x80x2-dimethyl, S,Sxe2x80x2-diethyl, S,Sxe2x80x2-dipropyl, S,Sxe2x80x2-dibutyl, S,Sxe2x80x2-dipentyl, S,Sxe2x80x2-diphenyl, S,Sxe2x80x2-dibenzyl and S,Sxe2x80x2-diacetyl.
Cyclic Dithio Acetals and Ketals
Examples of cyclic dithio acetals and ketals include 1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.
Acyclic Monothio Acetals and Ketals
Examples of acyclic monothio acetals and ketals include O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or -S-phenyl and O-methyl-S-2-(methylthio)ethyl.
Cyclic Monothio Acetals and Ketals
Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.
Miscellaneous Derivatives
O-Substituted Cyanohydrins
Examples of O-substituted cyanohydrins include O-acetyl, O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
Substituted Hydrazones
Examples of substituted hydrazones include N,N-dimethyl and 2,4-dinitrophenyl.
Oxime Derivatives
Examples of oxime derivatives include O-methyl, O-benzyl and O-phenylthiomethyl.
Imines
Substituted Methylene Derivatives, Cyclic Derivatives
Examples of substituted methylene and cyclic derivatives include oxazolidines, 1-methyl-2-(1xe2x80x2-hyd roxyalkyl)imidazoles, N,Nxe2x80x2-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles, diethylamine adducts, and methylaluminum bis(2,6-di-t-butyl4-methylphenoxide)(MAD)complex.
Monoprotection of Dicarbonyl Compounds
Selective Protection Of xcex1-and xcex2-Diketones
Examples of selective protection of xcex1-and xcex2-diketones include enamines, enol acetates, enol ethers, methyl, ethyl, 1-butyl, piperidinyl, morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, benzyl, S-butyl, and trimethylsilyl.
Cyclic Ketals, Monothio and Dithio Ketals
Examples of cyclic ketals, monothio and dithio ketals include bismethylenedioxy derivatives and tetramethylbismethylenedioxy derivatives.
Protection for the Carboxyl Group
Esters
Examples of esters include the following.
Substituted Methyl Esters
Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahyd ropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, xcex2-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl.
2-Substituted Ethyl Esters
Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl, 2-haloethyl, xcfx89-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2xe2x80x2-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, xcex1-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and benzyl.
Substituted Benzyl Esters
Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.
Silyl Esters
Examples of silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, 1-propyidimethylsilyl, phenyidimethylsilyl and di-t-butylmethylsilyl.
Activated Esters
Examples of activated esters include thiols.
Miscellaneous Derivatives
Examples of miscellaneous derivatives include oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt(III) complex.
Stannyl Esters
Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.
Amides and Hydrazides
Amides
Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.
Hydrazides
Examples of hydrazides include N-phenyl and N,Nxe2x80x2-diisopropyl hydrazides.
D. Synthetic Chemical Examples
Additional experimental descriptions of the compounds of the invention are found in the Examples of U.S. Pat. No. 4,861,897, incorporated herein by reference in its entirety. Examples 3, 4, 6, 7, 8, and 9 below correspond to Examples 1,2, 13, 7, 8, and 14 of the ""897 patent, respectively, and are provided as general guidance.